Bulky Pd-NHC Catalysts for Cross-Coupling Reactions

Cross-Coupling Catalysts
DOI: 10.1002/anie.201106131
The Development of Bulky Palladium NHC Complexes
for the Most-Challenging Cross-Coupling Reactions
Cory Valente, SelÅuk C¸ alimsiz, Ka Hou Hoi, Debasis Mallik, Mahmoud Sayah,
and Michael G. Organ*
Angewandte
Chemie
Keywords:
bulky ligands · cross-coupling ·
homogeneous catalysis ·
N-heterocyclic carbenes ·
PEPPSI
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Reviews
M. G. Organ et al.
3314 www.angewandte.org 2012 Wiley-VCH Verlag GmbH Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2012, 51, 3314 – 3332

1. Introduction
The 2010 Nobel Prize in Chemistry was awarded jointly to
Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki “for
palladium-catalyzed cross-couplings in organic synthesis”.[1]
This chemical tool has improved the capabilities of the
organic chemist to form CÀC bonds with precision under mild
reaction conditions,[2]
and has benefited greatly of late with
advancements in ligand design. Although phosphine-
based ligands have been investigated most intensively
so as to improve the catalytic proficiency in cross-
coupling reactions, recently N-heterocyclic carbene
(NHC) ligands have generated attention in light of
many favorable attributes, including the relatively high
thermal stability of the PdÀNHC bond.[3,4]
The strong
binding of the electron-rich carbene to the metal center
helps the palladium retain its ligand, the consequence
of which is longer catalyst lifetime and a consistent
reactivity throughout the course of the transformation.
A number of monoligated palladium NHC complexes
have been prepared and demonstrated to have high
levels of reactivity as reported notably by Caddick and
Cloke,[5]
Bellemin-Laponnaz and Gade,[6]
Nolan,[7,8]
Beller,[9]
Herrmann,[10]
and Organ[11]
(Figure 1). The
activities of complexes 1–14 have been correlated with
the steric environment around Pd; in general, the
bulkier the NHC (typically IPr had ideal structural and
electronic properties for general use), the higher the
catalytic activity.[12,13]
Based on empirical data, Espinet
and co-workers previously suggested that bulky ligands
tend to promote a tri-coordinated palladium inter-
mediate thereby lowering the overall activation energy
in cross-coupling reactions.[14]
In a recent computa-
tional study of the alkyl–alkyl Negishi reaction,[13,15]
the
Organ group demonstrated that an increase in steric
bulk close to the metal center can play a role in
promoting more than one step of the catalytic cycle, but
that the largest effect is seen in transmetalation, which
is viewed to be rate-limiting for at least that particular
coupling.
Over the course of the last five years, Organ and co-
workers developed a family of air-stable, user-friendly
palladium NHC pre-catalysts and sys-
tematically varied the electronic and
steric properties about the metal
center to independently fine-tune the
propensity for palladium to oxidatively
insert and reductively eliminate with comparable effi-
ciency.[16–18]
The first-generation pre-catalysts (12–14) in the
Pd-PEPPSI series (PEPPSI is an acronym for pyridine-
enhanced precatalyst preparation, stabilization, and initia-
tion) are prepared in air by heating their precursor azolium
salts with PdCl2 and K2CO3 in neat 3-chloropyridine to
provide near quantitative yields of the corresponding Pd-
PEPPSI complexes (Scheme 1).[11–13]
Palladium-catalyzed cross-coupling reactions enable organic chem-
ists to form CÀC bonds in targeted positions and under mild condi-
tions. Although phosphine ligands have been intensively researched, in
the search for even better cross-coupling catalysts attention has
recently turned to the use of N-heterocyclic carbene (NHC) ligands,
which form a strong bond to the palladium center. PEPPSI (pyridine-
enhanced precatalyst preparation, stabilization, and initiation) palla-
dium precatalysts with bulky NHC ligands have established them-
selves as successful alternatives to palladium phosphine complexes.
This Review shows the success of these species in Suzuki–Miyaura,
Negishi, and Stille–Migita cross-couplings as well as in amination and
sulfination reactions.
From the Contents
1. Introduction 3315
2. Applications of Pd-PEPPSI
Catalysts in Cross-Coupling
Reactions 3316
3. Summary 3329
Figure 1. A selection of monoligated palladium NHC complexes used in palladium-
catalyzed cross-coupling reactions.
[*] Dr. C. Valente, Dr. S. C¸alimsiz, K. H. Hoi, Dr. D. Mallik, M. Sayah,
Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, ON M3J 1P3 (Canada)
E-mail: organ@yorku.ca
Cross-Coupling Reactions
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3315Angew. Chem. Int. Ed. 2012, 51, 3314 – 3332 2012 Wiley-VCH Verlag GmbH Co. KGaA, Weinheim

In particular, the effects that the carbene ligand has on
catalyst performance in Negishi,[19]
Suzuki–Miyaura,[11]
and
Kumada–Tamao–Corriu[20]
cross-coupling reactions as well as
Buchwald–Hartwig–Yagupolskii[21]
amination have been
investigated.[22]
Consistent with catalyst steric bulk being
important, yields obtained using Pd-PEPPSI-IPr (14) were
much greater than those obtained when using the less bulky
Pd-PEPPSI-IEt (13) or Pd-PEPPSI-IMes (12) pre-catalysts.
The role that steric effects play in the activity of Pd-PEPPSI-
IPr (14) has been investigated using a variety of techniques,
including computation[13,15,17]
and NMR spectroscopy.[23]
Since
the s-donor abilities of IMes, IEt, and IPr carbenes are
similar,[15]
steric factors are likely at work in the improved
performance of 14.
More recently, attention has been put on further increas-
ing the steric bulk at the ortho positions of the N-phenyl
moieties of the NHCs as this might continue the trend and
lead to further increases in catalyst reactivity. On the basis of
this hypothesis, second-generation Pd-PEPPSI complexes,
namely Pd-PEPPSI-IBu (15), Pd-PEPPSI-IPent (16), and Pd-
PEPPSI-cPent (17) were synthesized (Figure 2).[18]
2. Applications of Pd-PEPPSI Catalysts in Cross-
Coupling Reactions
It has been repeatedly shown that Pd-PEPPSI-IPr (14) is
an efficient and versatile catalyst in cross-coupling reac-
tions.[12,13,24,25]
However, limitations remain in a handful of
difficult but useful cross-coupling reactions. Based on liter-
ature reports and unpublished results, attention was focused
on what are generally regarded to be some of the most
challenging cross-coupling and amination reactions in order
to evaluate and compare catalysts 14–17. These include
1) Suzuki–Miyaura and 2) Negishi cross-couplings reactions
to produce tetra-ortho substituted (hetero)biaryl compounds,
3) Negishi cross-coupling reactions of secondary alkylzinc
halides with aryl halides, 4) Stille–Migita cross-couplings of
heteroaryl stannanes with aryl halides, 5) Buchwald–Hart-
wig–Yagupolskii aminations under mildly basic conditions,
Cory Valente obtained a HBSc in biological
chemistry from York University in 2003
before pursuing a Ph.D. in organic chemistry
with Professor Michael G. Organ at the
same institution (NSERC scholarship). His
PhD work on the total synthesis of neodola-
bellane-type diterpenoids and Pd-catalyzed
cross-coupling reactions was awarded the
2009 Governor Generals Gold Medal. As a
postdoc at Northwestern University with Sir
Fraser Stoddart, he worked on the synthesis
of new carbon allotropes, conformational
control in polyrotaxanes, and on novel appli-
cations of metal–organic frameworks. He is currently a Senior Chemist in
the Advanced Materials Division of The Dow Chemical Company.
SelÅuk C¸ alimsiz studied chemistry at the
Ankara University, Faculty of Sciences. In
2003, he completed his MSc in Professor
George M. Bodner’s Group at Purdue Uni-
versity, with a scholarship from the Republic
of Turkey, Ministry of Education. He com-
pleted his PhD with Professor Mark A.
Lipton at Purdue University on the total
synthesis of Callipetins and Papuamides. In
2007, he joined Professor Michael G.
Organ’s group. His work focused on the
development of Pd-PEPPSI-IPent precatalyst
and its applications in various cross-coupling
reactions. Currently, he is working as a Research Scientist at Gilead in
Alberta, Canada.
Debasis Mallik has a BSc in Chemistry from
Presidency College, Kolkata, India and an
MSc from the Indian Institute of Technology,
Kanpur, India. For his PhD he moved to
York University in Toronto (Canada) under
the supervision of Professor Michael G.
Organ where he studied the silicon-mediated
[2+2] photocyclization reaction and its use
in total synthesis. In 2003 he joined Total
Synthesis Ltd. in Toronto (Canada) where he
led several industrial and academic projects
including the development of the Pd-
PEPPSI-IPent precatalyst. Currently, he is
working with Professor Organ toward the automation of the microwave-
assisted continuous-flow organic synthesis (MACOS) system for commercial
applications.
Ka Hou Hoi was born in China in 1985. In
2007, he obtained a BSc in biological
chemistry from York University in Toronto
(Canada). He is currently pursuing a PhD in
organic chemistry under the supervision of
Professor Michael G. Organ at the same
institution. His main research interests
include transition-metal-catalyzed cross-cou-
pling reactions, in particular the Pd NHC
catalyzed CÀN bond formation and elucida-
tion of its mechanism.
Scheme 1.
Figure 2. Second-generation Pd-PEPPSI complexes with increased
steric bulk on the NHC.
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M. G. Organ et al.

and 6) sulfination reactions of electronically and sterically
deactivated aryl and heteroaryl halides and sulfides. In this
Review, state-of-the-art palladium-catalyzed methods for
these cross-coupling reactions will be summarized, and then
head-to-head comparison experiments of Pd-PEPPSI com-
plexes (and when relevant other ligand systems) will be
presented along with a general survey of the most active
catalyst in this series to date, Pd-PEPPSI-IPent (16).
2.1. Suzuki–Miyaura Cross-Coupling Reactions for the Formation
of Tetra-ortho-Substituted (Hetero)biaryl Compounds
The cross-coupling of organoboron reagents with organic
electrophiles is generally accepted as the most widely used
coupling method in light of the commercial availability of a
wide selection of air- and moisture-stable boronic acids, the
limited toxicity of these reagents and their by-products, and
the mild reaction conditions that can be employed which
tolerate a variety of functional groups. One of the most
challenging couplings remains the formation of tetra-ortho-
substituted biaryl compounds, especially under mild reaction
conditions. In 1997, Johnson and Foglesong reported the
preparation of an unsymmetrical tetra-ortho-substituted
biaryl in 12% overall yield using [Pd(PPh3)4] and Na2CO3
as the base (Scheme 2, no temperature was given).[26]
More
recently, Buchwald and co-workers reported Suzuki–Miyaura
reactions for the synthesis of tetra-ortho-substituted biaryl
compounds from aryl bromides using hindered biarylphos-
phine ligands 18, 19, and 20 in conjunction with [Pd2(dba)3]
(dba = dibenzylideneacetone) at 1108C (Scheme 3).[27]
In
2004, a similar series of biaryl compounds were prepared by
Glorius and co-workers in which they coupled substituted aryl
chlorides and boronic acids using their bioxazoline-derived
ligand IBiox12·HOTf (21) with Pd(OAc)2 at 1108C
(Scheme 4).[28]
In 2008, Hoshi, Hagiwara, and co-workers
reported the use of ruthenocenylphosphine RPhos (22) with
[Pd2(dba)3] to provide three tetra-ortho-substituted biaryl
compounds from aryl chlorides and boronic acids at 1008C
(Scheme 5).[29]
The requirement for high reaction temper-
atures places limitations on this methodology. Thus, the
development of a catalyst that could perform such conver-
sions at a relatively low reaction temperature would be a
Mahmoud Sayah completed his undergradu-
ate and masters studies in 2006 at the
Department of Organic Chemistry, Stock-
holm University (Sweden). In 2007 he
joined the group of Professor Michael G.
Organ at York University, Toronto (Canada)
as a PhD student. His research focus is on
the synthesis and catalytic applications of
organometallic reagents. He has made con-
tributed to the development of the Pd-
PEPPSI-IPent precatalyst and its use in the
formation of CÀC and CÀS bonds.
Michael G. Organ is professor for organic
chemistry at York University in Toronto
(Canada). His research focuses on synthetic
efficiency and its application to catalysis,
natural products synthesis, and flow chemis-
try. His group has pioneered the develop-
ment of a new, highly efficient Pd catalyst
system based on the N-heterocyclic carbene
ligand system. Pd-PEPPSI-IPr, launched in
2006, and Pd-PEPPSI-IPent, introduced in
2009, are the two primary members of this
catalyst family. He has also developed the
concept of microwave-assisted, continuous-
flow organic synthesis.
Scheme 2. Bz=benzoyl.
Scheme 3. Cy=cyclohexyl.
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considerable advancement in the production of sterically
congested and functionalized biaryls.
Pd-PEPPSI complexes were evaluated in a model reac-
tion, the coupling of 2,6-dimethylphenylboronic acid (23) and
1-bromo-2-methoxynaphthalene (24; Table 1). Initial studies
were conducted on two base/solvent systems: KOH/dioxane
and KOtBu/tBuOH. The KOH/dioxane system at 658C with a
slight excess of arylboronic acid (1.2 equiv) and 2 mol% Pd-
PEPPSI-IPr (14) delivered the desired product (25) in 41%
yield (Table 1, entry 1). Under the same reaction conditions,
Pd-PEPPSI-IPent (16) led to 91% yield of 25 (Table 1,
entry 2), while the subtly less-hindered derivatives Pd-
PEPPSI-IBu (15) and Pd-PEPPSI-cPent (17) provided 4
and 9% yields, respectively (Table 1, entries 3 and 4).
These initial results are consistent with previous findings
that the steric topography around the palladium atom is
crucial. It has been recognized that the bulk around the metal
must be “fluid” or “conformationally flexible” to exert a
positive influence on the cross-coupling process.[13,15–18,28,30]
A
systematic series of investigations has revealed the following
factors that are essential for useful catalyst turnover of Pd-
NHC complexes:
1) branching at the benzylic carbon of the ortho-alkyl
substituent is necessary (compare IMes (as in 12) versus
IPr (in 14) and IBu (in 15) versus IPent (in 16))
2) increasing the steric bulk, provided Point 1 is satisfied,
improves catalyst performance (compare IPr (in 14)
versus IPent (in 16))
3) flexible steric bulk in the alkyl substituent is essential,
(compare IPent (in 16) versus cPent (in 17)).
Pd-PEPPSI-IPr (14) and Pd-PEPPSI-IPent (16) were next
evaluated in a head-to-head comparison study for the
coupling of a variety of hindered aryl bromides and aryl
chlorides with hindered arylboronic acids using KOtBu in
tBuOH in the presence of 4 Š molecular sieves (Scheme 6).[31]
Pd-PEPPSI-IPent (16) proved to be an excellent catalyst for
these demanding cross-coupling reactions to form tetra-ortho-
substituted biaryls in good yields under relatively mild
reaction conditions. Substituents in the ortho position, such
as methyl, primary alkyl, phenyl, fluorine, and alkoxy groups
were accommodated. With few exceptions, Pd-PEPPSI-IPr
(14) provided considerably lower product yields under
identical reaction conditions. In certain cases, Pd-PEPPSI-
IPent (16) is active enough to provide useful turnover at room
temperature to give tetra-ortho-substituted biaryl products
(Scheme 6).[18]
2.2. Negishi Cross-Coupling Reactions for the Formation of Tetra-
ortho-Substituted (Hetero)biaryl Compounds
Mild and efficient preparative routes for organozinc
reagents, their superb functional group tolerance, and mild
reaction conditions makes the Negishi cross-coupling reaction
an attractive alternative and viable method to prepare the
biaryl motif.[32]
In 2001, Dai and Fu reported the first general
method for palladium-catalyzed Negishi couplings between
arylzinc reagents and (hetero)aryl chlorides that provided
Scheme 4. Tf=trifluoromethanesulfonyl.
Scheme 5.
Table 1: Evaluation of Pd-PEPPSI complexes 14–17 in the Suzuki–
Miyaura coupling to provide tetra-ortho-substituted biaryl compounds.
Entry Pd-PEPPSI-Catalyst Conversion [%][a]
1 Pd-PEPPSI-IPr (14) 41
2 Pd-PEPPSI-IPent (16) 91
3 Pd-PEPPSI-IBu (15) 4
4 Pd-PEPPSI-cPent (17) 9
[a] Percent conversion was assessed by GC analysis using undecane as a
calibrated internal standard; reactions were performed in duplicate.
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good yields in the presence of [Pd(PtBu3)2] in THF/NMP at
1008C (Scheme 7).[33]
In 2004, Milne and Buchwald prepared
a variety of sterically bulky biaryl compounds that contained
functional heterocycles by coupling (hetero)aryl halides with
arylzinc reagents that were prepared in situ using the
hindered RuPhos ligand (26) in conjunction with [Pd2(dba)3]
at 708C (Scheme 8).[34]
In 2006, Organ and co-workers
developed a user-friendly Negishi method capable of cross-
coupling arylzinc halides with aryl bromides and chlorides in
excellent yields using Pd-PEPPSI-IPr (14) under mild reac-
tion conditions (Scheme 9).[19]
Similarly, in 2008, Knochel and
co-workers reported a one-pot method employing Pd-
PEPPSI-IPr (14) to form (hetero)biaryl compounds from in
situ generated (hetero)arylzinc reagents and aryl bromides,
Scheme 6.
Scheme 7. NMP=N-methylpyrrolidone.
Scheme 8.
Scheme 9.
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chlorides, and triflates under relatively mild reaction con-
ditions (Scheme 10).[25]
In a series of publications, Knochel
and co-workers also reported Negishi reaction conditions for
coupling organozinc reagents with aryl halides bearing
relatively acidic protons using Pd(OAc)2 in conjunction with
Buchwalds SPhos ligand (20) (Scheme 11).[35]
A comparative study of Pd-PEPPSI-IPent (16), Pd-
PEPPSI-IPr (14), and the well-tailored dialkylbiaryl phos-
phine ligands 20 and 27 [Pd source = Pd2(dba)3] in the
coupling of 2-mesitylzinc halide with 1,3-dimethyl-2-bromo-
benzene was conducted (Figure 3).[36]
In this study, each
reaction was prematurely terminated at 2.5 h to give a
snapshot of the species present and to allow room for a
temperature study. At room temperature, only the NHC-
based catalysts were active under these mild reaction
conditions, with Pd-PEPPSI-IPent (16) outperforming Pd-
PEPPSI-IPr (14). Turnover by all catalysts was achieved by
heating the reaction mixture to 708C in a THF/NMP co-
solvent system, wherein 14, 20, and 27 provided comparable
results (i.e., 45–55% desired product and a significant
quantity of homocoupling of the aryl bromide).[37]
Omitting
NMP had a detrimental effect on this cross-coupling reaction
for all the catalyst systems evaluated.
Pd-PEPPSI-IPent (16) and Pd-PEPPSI-IPr (14) were next
evaluated in a scope study of arylzinc reagents (prepared
in situ by transmetalation of organomagnesium bromides
with ZnCl2) with oxidative-addition partners bearing consid-
erable steric bulk and/or various functional groups at room
temperature or under mild heating (Scheme 12). Relatively
Scheme 10.
Scheme 11.
Figure 3. Comparison of catalysts 14 and 16 and ligands 20 and
27/[Pd2(dba)3] under various Negishi reaction conditions in the cross-
couplings leading to tetra-ortho-substituted biaryl compounds.
Scheme 12. TBS=tert-butyldimethylsilyl.
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M. G. Organ et al.

acidic species including anilines, phenols, alkyl alcohols, and
amides were well-tolerated. With few exceptions, 14 provided
considerably lower yields of cross-coupled products relative
to 16, which was also found to be active at 08C in
representative couplings.[36]
Using Pd-PEPPSI-IPent (16), the coupling between
heteroaryl halides and hindered arylzinc reagents was exam-
ined (Scheme 13). A variety of heterocyclic chlorides and
bromides were coupled in excellent yields; these included
pyrazine, quinoline, sterically bulky isoxazoles and pyrazoles,
as well as substituted pyrimidine, pyridazine, and pyridines.[36]
A variety of heteroarylzinc reagents, including 2-pyridyl,
4-isoquinolinyl, 2-thiophenyl, 2-thiazolyl, and 5-ethoxycar-
bonyl-2-furyl, were also effectively coupled with (hetero)aryl
bromides/chlorides at room temperature or under mild
heating (Scheme 14).[36]
2.3. Negishi Cross-Couplings of Secondary Alkylzinc Halides with
Aryl Halides
The cross-coupling between Csp2 and secondary Csp3
centers remains a challenge. During the last decade, a
number of groups have developed catalyst systems that are
uniquely suited for the coupling of secondary alkyl halides
with sp2
-hybridized aryl/alkenyl nucleophiles.[38]
On the other
hand, only a handful of studies have been published relating
to the equally useful cross-coupling of secondary Csp3-
hybridized organometallic species with aryl halides. One of
the major difficulties in this transformation remains b-hydride
elimination and migratory insertion (leading to 28a) that
competes with reductive elimination (leading to 28b) to
provide undesired product isomers (Figure 4).
From the mechanism, it is clear that changes to the
catalysts structure that speed up the rate of reductive
elimination will suppress b-hydride elimination and thus
isomerization. Several research groups have addressed this
Scheme 13.
Scheme 14.
Figure 4. Mechanism for the formation of branched (normal) alkyl-
substituted aryl products (28b) and linear (isomerized) alkyl-substi-
tuted aryl products (28a) by the transition-metal-catalyzed Negishi
cross-coupling of secondary alkylzinc halides with aryl halides.
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issue by employing catalysts containing bulky phosphine
ligands that increase the steric topography around Pd that
favorably positions the coupling fragments for the reductive
elimination. In 1972 and 1984, Kumada/Tamao[39]
and Hay-
ashi,[40]
respectively, reported that [NiCl2(dppp)] and [PdCl2-
(dppf)] complexes can couple secondary alkyl Grignard
reagents and in situ prepared secondary alkylzinc reagents
with a limited array of aryl halides (Scheme 15). In 2008,
Molander[41]
and Hoogenband[42]
independently reported the
Suzuki–Miyaura coupling of secondary alkyltrifluoroborates
with aryl halides in the presence of nBuPAd2 and RuPhos
(26), respectively (Scheme 16). These publications describe
primarily the efficient coupling of cyclic alkyltrifluoroborates,
which obscures whether isomerization has occurred or not;
when linear alkyltrifluoroborates were used the ratio of
desired to isomerized product was moderate and functional
group incompatibilities surfaced. Recently, Han and Buch-
wald published a report detailing the palladium-catalyzed
coupling of secondary alkylzinc halides with aryl bromides
and activated aryl chlorides using the bulky CPhos ligand
(29).[43]
Under their optimal conditions, good ratios of
secondary to primary alkyl (isomerized) couplings with
several substrates were observed, although the b-hydride
elimination pathway was not fully suppressed (Scheme 17).
As it is generally true that Group VIII transition-metal
complexes containing more-sterically hindered ligands
undergo reductive elimination faster than complexes with
less-hindered ancillary ligands,[44]
Pd-PEPPSI-IPent (16)
would be anticipated to perform well in the coupling of
secondary Csp3-hybridized organometallic complexes with aryl
halides. A series of ortho-, meta-, and para-substituted
bromobenzene derivatives was coupled with isopropylzinc
bromide in the presence of 1 mol% Pd-PEPPSI-IPr (14) or
Pd-PEPPSI-IPent (16) (Table 2). Pd-PEPPSI-IPent (16) pro-
vided good yields but, more importantly, it exhibited excellent
selectivity for the corresponding branched (30) over linear
(31) products. Conversely, while conversions were also high
with Pd-PEPPSI-IPr (14), the ratios of corresponding
branched-to-linear products were notably lower.[45]
Pd-PEPPSI-IPent (16) was also evaluated in a more
general sense using a variety of cyclic and acyclic secondary
alkylzinc reagents with several aryl halides (Scheme 18).
Excellent yields were obtained for a range of substrates.
Heteroaryl halides including pyridine, quinoline, pyridazine,
and benzothiazoles were coupled in high yields and functional
groups including aldehydes and nitriles that are susceptible to
undergo nucleophilic attack remained intact under these
reaction conditions. As in the model study, when acyclic
alkylzinc reagents were employed, the ratio of branched to
linear products remained good to excellent.[45]
Scheme 15.
Scheme 16.
Scheme 17.
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2.4. Stille–Migita Cross-Coupling Reactions at Low Temperature
The application of organostannanes in natural products
synthesis is well established because of their relatively
straightforward syntheses and shelf stability.[46]
The Stille–
Migita cross-coupling reaction has been employed to prepare
heterobiaryls, a common structural motif in various pharma-
ceutical agents,[47]
ligand systems for transition-metal catal-
ysis,[48]
and functional polymers.[49]
However, the stability of
the CÀSn bond that makes these reagents so practical to
handle renders them less reactive in catalysis, consequently
high temperatures (traditionally 1008C) are often required
for useful levels of conversion to be attained.[50]
The PEPPSI-
series of catalysts were evaluated with the goal of finding one
that is proficient in the Stille–Migita cross-coupling reaction
below 1008C.
In general, Pd-PEPPSI-IPent (16) was found to demon-
strate high efficiency over a variety of challenging (hetero)-
aryl halides with thiophene-, furan-, pyrrole-, piperizine-,
oxazole-, and thiazole-based organostannanes (Scheme 19).
Suzuki–Miyaura aryl–aryl coupling strategies involving het-
eroaromatic boronic acids (e.g., 2-thiophene boronic acid) are
often plagued with protodeboronation, especially in the
Table 2: Pd-PEPPSI-IPr (14) and Pd-PEPPSI-IPent (16) catalyzed Negishi
cross-coupling of iPrZnBr with aryl bromides: selectivity in branched/
linear product isomers.
Entry Ar-Br Catalyst Yield [%] 30/31
1 R=4-CN 14
16
85
92
3:1
27:1
2 R=4-CHO 14
16
64
78
6:1
39:1
3 R=4-COCH3 14
16
99
98
6:1
30:1
4 R=4-CO2CH3 14
16
83
99
5:1
40:1
5 R=4-OCH3 14
16
89
95
2.5:1
33:1
6 R=3-CN 14
16
77
84
1:1.4
11:1
7 R=3-CHO 14
16
78
71
1.6:1
22:1
8 R=3-OCH3 14
16
31
57
3.5:1
34:1
9 R=2-CN 14
16
99
80
1:8
2.4:1
10 R=2-OCH3 14
16
99
46
1:9
2:1
Scheme 18. Boc=tert-butyloxycarbonyl.
Scheme 19. [a] Reactions performed at 608C because of the poor
stability of the organostannanes.
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presence of a polar protic solvent.[51]
For sterically demanding
or electron-rich electrophiles, the oxidative-addition step
becomes sluggish and side reactions become a greater
concern. Drawing on experience with the cross-coupling
reactions of hindered boronic acids,[18]
it was envisioned that
the flexible bulk of the flanking isopentyl groups would
impart the steric properties necessary to facilitate reductive
elimination. Good-to-excellent yields for all thiophene-based
cross-coupling reactions were encountered, even at temper-
atures as low as 608C.[52]
These mild reaction conditions
facilitated the preparation of other sensitive motifs, such as
isooxazoles, benzothiazoles, sulfonamides, and furans. A
serious limitation in synthesizing substituted furans is the
facile decomposition of furan metalloids (e.g., 2-furanboronic
acid and the corresponding trifluoroborate salt) under polar,
protic conditions.[53]
This phenomenon is the reason why
primarily reactive electrophilic partners, such as iodo and
bromo-(hetero)aryl systems, have been most commonly
reported as coupling partners for these organometallic
species. The optimized conditions worked well for the
coupling of 2-furyl organostannane reagents with less-reac-
tive aryl bromides and chlorides. In addition, the method was
compatible with reactive functional groups, such as sulfona-
mide and ketone moieties, illustrating the catalytic efficiency
and versatility of Pd-PEPPSI-IPent (16).
The reactions proceeded equally well to give a variety of
pyrrole-based biaryl compounds in excellent yields from a
diverse array of oxidative addition partners, including hin-
dered (hetero)aryl bromides. It is noteworthy that poisoning
of the Pd catalyst,[54]
which is the common cause for the failure
of pyrrole-based cross-coupling reactions, was not observed
with Pd-PEPPSI-IPent (16). The conditions also worked well
for substrates containing multiple heteroatoms (e.g., thia-
zoles, oxazoles, piperizines) that are even more challenging.
The desire to lower the temperature of the Stille–Migita
cross-coupling reaction is inspired, in part, by the “thermally
delicate” nature of many potentially valuable cross-coupling
partners (e.g., thiazoles or oxazoles-based organotin com-
pounds). A thorough screening of various reaction conditions
revealed that coupling can occur at as low as 408C without
any compromise in yield. For example, 2-(tributylstannyl)th-
iophene was coupled with 2-chloropyrazine quantitatively at
408C using Pd-PEPPSI-IPent (16). A further reduction in
temperature to 308C for this coupling was possible using Pd-
PEPPSI-SIPr.[55]
2.5. Buchwald–Hartwig–Yagapol’skii Aryl Amination under Mild
Reaction Conditions
The palladium-catalyzed aryl amination reaction has
become one of the most valuable synthetic tools for the
construction of the CÀN bond.[56]
Since the discovery of the
first catalytic aryl amination reaction,[57]
extensive efforts
have been made towards the development of optimal catalyst/
ligand systems to improve reaction efficiency. By far, bulky
tertiary phosphines have shown the widest applicability for
this transformation.[58]
Some remarkable ligands (Figure 5)
that are highly active in the amination of aryl halides/pseudo
halides include Koies PtBu3,[59]
Bellers monodentate N-
substitued heteroarylphosphines,[60]
Buchwalds biaryl phos-
phines,[61]
Hartwigs ferrocenyl dialkylphosphines,[62,63]
Ver-
kades and Kwongs amino phosphines,[64]
and Stradiottos
phenylene-bridged P,N ligands.[65]
Conversely, NHC-type
ligands have been much less explored for this transforma-
tion.[3,8,21,66,67]
The generally accepted mechanism for this transforma-
tion is depicted in Figure 6.[68]
Several studies support amine
coordination and/or the deprotonation of the subsequent
metal ammonium complex as the rate-limiting step in this
catalytic cycle.[21,67,69]
Hence, strong bases are frequently
employed to facilitate the rate-limiting step.[63,70]
For example,
Hartwig and co-workers succeeded in coupling (hetero)aryl
halides with primary amines in the presence of NaOtBu or
Figure 5. A selection of bulky, highly active phosphine ligands utilized
in palladium-catalyzed aryl aminations.
Figure 6. Putative mechanism for the palladium-catalyzed amination
reaction.
.AngewandteReviews
M. G. Organ et al.

lithium bis(trimethylsilyl)amide with Josiphos (35)/Pd(OAc)2
(Table 3).[63]
The more challenging reaction involving the
coupling of aniline and aminoheterocycles was also achieved
under similar strongly basic reaction conditions
(Scheme 20).[71]
Poor functional-group tolerance was
observed, and so the development of mildly basic reaction
conditions at low temperature is of interest to broaden the
scope of this useful reaction.
To this end, Buchwald and co-workers developed a
method for the coupling of electron-deficient anilines with
aryl chlorides using K2CO3 base at 1108C (Scheme 21).[72]
Presumably, electron-withdrawing substituents act to lower
the pKa of the palladium ammonium complex into a range
suitable for deprotonation by the “weaker” carbonate base.
Another efficient method was developed by the same
research group that allowed an array of (hetero)aryl mesy-
lates to be transformed into the corresponding N-aryl amides
in moderate-to-excellent yields (Scheme 22).[73]
Recently, Pd-
PEPPSI-IPr (14) has been shown to be an effective and
versatile precatalyst for aryl aminations in the presence of
Cs2CO3 in DME.[21]
Using the optimized conditions developed for Pd-
PEPPSI-IPr (14),[21]
a variety of challenging aryl chlorides
were coupled with secondary amines (Scheme 23). Consis-
tently, Pd-PEPPSI-IPent (16) outperformed Pd-PEPPSI-IPr
(14).[67]
While 14 showed no activity in the coupling of
morpholine to 2-chloro-5-methoxy-1,3-dimethylbenzene,
Table 3: Cross-coupling of (hetero)aryl halides with primary amines
catalyzed by Pd(OAc)2 and Josiphos (35) (1:1) in toluene.
Entry Ar-R1
X R2
Cat. [%] Yield [%]
1 2-Py Cl octyl 0.01 98
2 3-Py Cl octyl 0.05 98
3 3-Py Cl 4-tolylamino 0.1 66
4 Ph Cl octyl 0.05 99
5 4-Tol Cl iBu 0.02 99
6 2-Py Br octyl 0.01 92
7 3-Py Br Bn 0.01 99
8 Ph Br Bn 0.005 99
9 3-Py I iBu 0.2 99
10 2-Tol I cyclohexyl 0.05 93
Scheme 20.
Scheme 21.
Scheme 22.
Angewandte
Chemie

which is both electronically and sterically disfavored, 16
provided excellent yields.
To shed some light on the differences in the catalytic
performance between Pd-PEPPSI-IPr (14) and Pd-PEPPSI-
IPent (16) with alkyl amine substrates, a rate study was
conducted (Figure 7) for the amination of a range of p-
substituted aryl chlorides with morpholine.[67a]
The bulkier
Pd-PEPPSI-IPent outperformed Pd-PEPPSI-IPr in each test
case and in all instances, 16 reached maximum turnover in a
shorter timeframe, and coupled even the most electron-rich
aryl chlorides where Pd-PEPPSI-IPr (14) failed.
A more detailed kinetic study for alkyl amines was
conducted wherein the loading of 14 was held constant while
the concentrations of 4-chlorobenzonitrile, morpholine, and
Cs2CO3 were systematically varied (Figure 8). When the
concentration of morpholine was doubled (Figure 8b), the
Scheme 23.
Figure 7. Substituent effects on the rate of amination of para-substi-
tuted aryl chlorides with morpholine catalyzed by a) Pd-PEPPSI-IPr (14)
or b) Pd-PEPPSI-IPent (16).
Figure 8. Determining the effect of electrophile, nucleophile, and base
on the rate of amination of para-chlorobenzonitrile with morpholine
catalyzed by Pd-PEPPSI-IPr (14). a) Base and morpholine held constant
while varying [para-chlorobenzonitrile]. b) para-Chlorobenzonitrile and
base held constant while varying [morpholine]. c) para-Chlorobenzoni-
trile and morpholine held constant while varying [Cs2CO3].
.AngewandteReviews
M. G. Organ et al.

maximum rate increased by approximately 20%, suggesting
that amine coordination to palladium is relevant, but not rate-
limiting. While the reaction was marginally less than zero
order in aryl chloride, the rate was significantly influenced by
increasing the equivalents of Cs2CO3 (Figure 8c). Doubling
the base equivalents resulted in an approximate doubling of
the maximum rate, which is consistent with the deprotonation
step being rate limiting in the catalytic cycle.
To get a more detailed analysis of aminations involving
aniline derivatives, which are far less basic and therefore more
acidic, rate studies were again carried out.[67b]
The conse-
quence of substituent effects on the rate of the aryl amination
reaction with aniline and electronically dissimilar aryl chlor-
ides was found to follow the expected trajectories for both Pd-
PEPPSI-IPr (14) and Pd-PEPPSI-IPent (16) (Figure 9). As
was found in the coupling with morpholine, aryl chloride
concentration has little effect on the reaction rate (Fig-
ure 10a), which is unsurprising given the strong s-donating
properties of the NHC ligand. However, it was found that
both the concentration of aniline and the equivalents of base
had an apparent first-order effect on the rate of reaction
(Figure 10b and c). In combination with the morpholine-
based rate studies, it appears that the nature of the amine
determines whether the formation of the palladium ammo-
nium complex or deprotonation of this complex is rate-
limiting. Intuitively this situation can be rationalized in that
the more nucleophilic the amine (i.e., morpholine relative to
aniline), the easier it is to overcome the energy barrier to yield
the palladium ammonium complex, which should be more
stable from a standpoint of inductive effects. On the other
hand, aniline and its derivatives have a lower pKa (ca. 25)
relative to morpholine (ca. 36) and thus their corresponding
palladium ammonium complexes (pKa much less than 10) are
Figure 9. Substituent effects on the rate of the aryl amination reaction
of para-substituted aryl chlorides with aniline as catalyzed by a) Pd-
PEPPSI-IPr (14) and b) Pd-PEPPSI-IPent (16).
Figure 10. Determining the effect of electrophile, nucleophile, and base
on the rate of aryl amination of para-anisole with aniline catalyzed by
Pd-PEPPSI-IPent (16). a) Base and aniline held constant while varying
[para-anisole]. b) para-Anisole and base held constant while varying
[aniline]. c) para-Anisole and aniline held constant while varying
[Cs2CO3].
Angewandte
Chemie

more readily deprotonated. Looking more closely, a rate
study on the amination of chlorobenzene with various para-
substituted anilines reveals that electron-poor anilines per-
form poorly in the presence of either Pd-PEPPSI-IPr (14) or
Pd-PEPPSI-IPent (16; Figure 11). Given that electron-poor
anilines are more acidic, this study suggests that amine
coordination to palladium may be more crucial than depro-
tonation.
Regardless of the mechanistic underpinnings, an array of
electron-deficient anilines were successfully coupled with
electron-rich aryl chlorides in good-to-excellent yields
(Scheme 24). This is a noteworthy set of reactions as it
represents, based on the rate studies, the worst electronic-
pairing scenario (electron-rich aryl chlorides and electron-
deficient anilines) for this transformation. This highlights the
high reactivity of Pd-PEPPSI-IPent (16) in the aryl amination
reaction. Relating to the point made above about coordina-
tion being more important for anilines owing to their poor
basicity, it is of note that Pd-PEPPSI-IPr (14) failed to provide
any product for p-cyanoaniline when the strong base KOtBu
was used whereas Pd-PEPPSI-IPent (16) provided a 70%
yield for this identical transformation. Strikingly, 16 provided
50% yield even when carbonate base was used! This result is
strongly suggestive that there may be more than just steric
effects around the metal center at play that gives 16 some of
its high reactivity in this transformation.
2.6. Carbon–Sulfur Bond Formation at Low Temperature
Carbon-heteroatom bond formation in cross-couplings is
dominated by aryl aminations, however examples exist for the
formation of aryl ethers and thioethers which themselves are
important and common functional groups in natural products
and pharmaceuticals.[74]
Cross-coupling methods to produce
thioethers typically require elevated reaction temperatures to
achieve useful conversion into products,[75]
with the Josiphos
ligand (35) being the most generally applied ligand.[75e,76]
Building on the reasoning presented in the preceding
Sections, Pd-PEPPSI-IPent (16) was examined for its ability
to perform the thiolation of electrophiles at room temper-
ature or below. An impediment in this class of cross-coupling
reactions is the thiolate-derived siphoning of palladium away
from the catalytic cycle into catalytically inactive palladium
adducts (i.e., [ArPd(SR)2]À
and the dimeric thiolate-bridged
[(ArPdSR)2]).[76c]
To circumvent these resting states, reductive
elimination must be fast and this would be aided by the ideal
steric topography of 16.
Sulfination of (hetero)aryl halides with aryl sulfides
proceeded efficiently at 408C to provide various diaryl
thioethers under the mildest reactions conditions reported
to date for this transformation (Scheme 25).[77]
Both aryl
bromides and aryl chlorides (the chlorides required additional
base for optimal results) possessing heteroatoms and/or steric
bulk were routinely coupled to provide high yields of product.
Alkyl thiols, which are known to be sluggish coupling
partners, were found to be as effective as aryl thiols in this
cross-coupling methodology (Scheme 26); all substitution
patterns, including primary, secondary, and tertiary alkyl
Figure 11. Substituent effects on the rate of the aryl amination reaction
of chlorobenzene with para-substituted anilines as catalyzed by a) Pd-
PEPPSI-IPr (14) and b) Pd-PEPPSI-IPent (16).
Scheme 24.
.AngewandteReviews
M. G. Organ et al.

thiols were tolerated.[77]
The functional triisopropylsilane-
thiol, a masked form of sulfur, was also routinely coupled
despite its significant steric component and, as pioneered by
Hartwig and co-workers, is a viable route to install free thiols
onto sp2
-hydridzied carbon centers.[78]
A rate study revealed that most cross-couplings were
complete within 4–5 h, despite the standard reaction being
run for a full 24 h. This encouraged the evaluation of aryl
sulfinations at room temperature, and even sterically hin-
dered substrates fared well (Scheme 27). This developed
route is the mildest and most generally applicable set of
reaction conditions reported to date for the formation of thiol
ethers by metal-catalyzed sulfinations.
3. Summary
Since their first reported use as ligands for palladium in
cross-coupling reactions just over a decade ago, NHCs have
come a long way from chemical curiosities to mainstream,
commercially available ligands for catalysis. The NHC metal
precatalyst complexes are very stable to air and moisture and
have shown superb reactivity in a growing number of
applications. Increased steric bulk on the NHC that buries
the metal deep within its fold has been linked to heightened
reactivity in cross-coupling procedures. Detailed analysis of
these structural studies has led to the creation of a number of
unique imidazole-based carbene palladium complexes in
which the degree of steric bulk has been steadily increased.
This approach has led to the creation of Pd-PEPPSI-IPent
(16), which has been demonstrated to be among the most
reactive and general catalysts for Suzuki–Miyaura, Negishi,
and Stille–Migita couplings for carbon–carbon bond forma-
tion and in amination and sulfination reactions for carbon–
heteroatom bond formation.
Received: August 30, 2011
Published online: January 27, 2012
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Scheme 27.
Angewandte
Chemie

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